Cachexic muscle wasting-a complication frequently associated with cancer, AIDS, sepsis, diabetes, chronic renal failure, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), sarcopenia and other inflammatory conditions, a debilitating and often life-threatening disorder for which there is currently no effective treatment. Recent studies have indicated that muscle wasting is caused primarily by excessive degradation of muscle protein through the ubiquitin-proteasome pathway. More specifically, several ubiquitin ligases within this pathway are rate-limiting in muscle protein breakdown, and their expression is increased in various catabolic states;thus, they are considered potential therapeutic targets for controlling muscle wasting. Moreover, as it is likely these ubiquitin ligases are responsible for normal protein turnover as well as muscle wasting, one promising strategy is to target the signaling pathways that upregulate these enzymes in pathological conditions, instead of directly inhibiting the enzymes. Catabolic cytokines represented by TNF-alpha are significant mediators of muscle wasting induced by inflammatory conditions;importantly, they are capable of upregulating key ubiquitin ligases implicated in muscle wasting. The current proposal is based on our preliminary findings, and has been designed to: 1) elucidate the signaling pathways that mediate the upregulation of key ubiquitin ligases via TNF-alpha- represented catabolic cytokines in inflammatory conditions and 2) evaluate experimental therapies through targeting the pathological signaling pathways in the animal models of muscle catabolism induced by inflammatory conditions, including cancer, diabetes, renal failure and sarcopenia. These objectives will be accomplished through execution of the following specific aims: Aim 1. To determine whether p38 MARK mediates atrogin-1/MAFbx upregulation and muscle catabolism induced by inflammatory conditions. Genetic and pharmacological approaches will be used to assess the role of p38 in atrogin-1/MAFbx-mediated muscle catabolism and the effect of blocking p38 on animal models of muscle catabolism. Aim 2. To determine the signaling mechanism that mediates p38 upregulation of the atrogin-1/MAFbx gene. How p38 influences the transcription of the atrogin-1/MAFbx gene at the molecular level will be analyzed. Aim 3. To determine the significance and signaling mechanism of UBR2/E3alpha-ll upregulation in muscle wasting induced by inflammatory conditions. Whether and how UBR1/E3alpha-ll mediates muscle wasting will be evaluated by using genetic approaches. The achievement of these three aims will facilitate our long-term goal: to develop effective therapeutic strategies in the treatment of myriad patients with cachexic muscle wasting.